Study Explores Genetics of Extreme Longevity

Exceptional longevity -- living to age 100 or more -- seems to be associated with a complex set of genetic factors, researchers said.

by Michael Smith Michael Smith North American Correspondent, MedPage Today
July 01, 2010

Action Points

Explain to interested patients that this study found that genetics plays an important role in the chance of living to be 100 or more, but caution that the findings have little immediate clinical application.

Exceptional longevity -- living to age 100 or more -- seems to be associated with a complex set of genetic factors, researchers said.

In a genome-wide association study that included almost 1,000 people ages 100 or older, a set of 150 single-letter variants in DNA -- involving about 70 different genes -- was able to distinguish between the centenarians and controls 77% of the time, according to Thomas Perls, MD, of Boston University, and colleagues.

The analysis by Perls and colleagues, reported online in the journal Science, found 19 clusters of variants associated with exceptionally long life that were correlated with differences in the prevalence and age of onset of conditions such as dementia and hypertension.

The authors noted that the average human lifespan in developed countries now ranges from 80 to 85 years.

"Environmental factors (lifestyle choices relating to diet, exercise, smoking habits, etc.) as well as genetic factors are believed to contribute to healthy aging. The results of human twin studies suggest that only 20% to 30% of the variation in survival to an age of about 85 years is determined by genetics," they wrote.

So although environmental factors are involved, "genetics is playing a very important role in the wonderful trait," Perls told reporters in a telephone press conference.

And Perls cautioned that the current study is not likely to lead to an "elixir" that could allow people to live to be 100 or more, largely because of the complex interactions among dozens of genetic variants that he and his colleagues found.

"This will not lead to treatments that will get a lot of people to become centenarians," he said, "but rather (will) make a dent in the onset of age-related diseases," although even that will require much more study.

Indeed, he said, the key to an extremely long life appears to be a capacity to delay the onset of age-related disability and diseases, such as cardiovascular disease (including stroke) and dementia. "Centenarians are a model of healthy aging, as the onset of disability in these individuals is generally delayed until they are well into their mid-nineties," Perls and colleagues wrote.

In their previous work, Perls and colleagues have shown that 90% of centenarians are disability-free until age 93 on average. The few people who lived to be 110 or older, Perls added, were able to "compress both disability and disease even further" into the last years of their lives.

The current genome-wide association study gives some clues as to how these individuals might have been able to achieve that, according to lead author Paola Sebastiani, PhD, also of Boston University.

One possible explanation, she said, might have been that centenarians had fewer genetic variants that predispose people to age-related illnesses. But a comparison of the prevalence of such "disease-associated variants" did not differ substantially between centenarians and controls, she said.

That suggests that the genetic variants associated with long life involve ways of overcoming the effects of disease-associated gene variants, she said.

The study is "very exciting for the whole field of genetics and genomics and personalized health care," said Kathryn Teng, MD, of the Cleveland Clinic, who was not involved in the study but who is director of clinical integration of personalized healthcare at the hospital.

"It can potentially give us a lot of information -- now, but also in the future -- to target wellness, and risk for disease and also to develop potential medications or treatments," she told MedPage Today in an interview at which a public information officer was present.

But, Teng cautioned, the data from the study are not ready for application in the clinic.

"From a clinical practice standpoint, when I'm seeing patients, this is really not useful and helpful right now," she said. Instead, doctors will likely have to continue doing what they have been doing -- counseling their patients on how to lead healthy lives.

Perls noted that the environmental impact on longevity is clear, bolstered by such things as the 88-year average life expectancy of Seventh-Day Adventists, whose religion requires some behaviors -- such as not smoking -- that lead to healthy aging.

But it's also clear -- from such things as family histories -- that genetics plays a role, he said.

To try to clarify the issue, he and colleagues studied the genes of 801 unrelated volunteers, ages 100 or more, who were part of the New England Centenarian Study, and compared them to 926 controls. To replicate any findings, they performed the same analysis on 254 people involved in another cohort of centenarians, as well as 341 controls.

In the discovery set, the researchers found 70 single nucleotide polymorphisms, or SNPs, that had a genome-wide significant association with a long life. Thirty-three of those were also significant in the replication set.

The list included only five SNPs associated with common diseases, the researchers said, and the risk variants of those SNPs were significantly less frequent in centenarians than in controls.

The findings suggested that many SNPs played a role in long life, but did not say anything about their interactions, the researchers noted. To try to nail that down, they constructed a predictive model, starting with the SNP most significantly associated with long life and adding others in a stepwise fashion.

The final model included 150 uncorrelated SNPs, including 77 found in known genes, the researchers said, and correctly identified 77% of the centenarians.

The 23% error rate, Sebastiani told reporters, might have arisen because other genetic factors -- not found in the study -- are playing a role in longevity. Or, she said, it might imply that genetics is not the only factor involved.

At the same time, she said, about 15% of the controls also appear to have a "predisposition to exceptional longevity" based on the genetic model -- a proportion considerably higher than one centenarian in 6,000 observed in the general population.

That could be because the controls in this analysis are not a representative sample of the general population, Sebastiani said.

On the other hand, the researchers noted online in Science, the finding is "consistent with the suggestion that many more people than previously suspected have the potential, at least genetically, to survive to an exceptional age."

Interestingly, the collection of so-called "longevity-associated variants" was not the same for all centenarians, the researchers found.

Instead, the centenarians were divided into 19 clusters whose members each shared similar sets of longevity-associated variants that differed noticeably from the others, suggesting there are multiple pathways to long life.

As well, the 19 clusters showed a clear age division, with the oldest centenarians mostly found in four of them. More than 75% of the volunteers in those four were older than 106, and they included 46% of the so-called "super-centenarians" -- those older than 110 -- in the overall cohort.

Interestingly, one cluster that included 30 centenarians had almost no longevity-associated variants, the researchers found. It's possible that's just good luck or healthy behavior, Perls and colleagues said, but it may also be true that rare genetic variants -- not in the original array of tested SNPs -- can take the credit.

That idea is bolstered by family histories, they said. Data were available for 17 of the members of the cluster, of whom 59% had a strong family history of longevity.

A closer look at the genes of those volunteers, said Perls and colleagues, "may be particularly fruitful."

The study was supported by the National Institute of Aging and the National Heart, Lung, and Blood Institute.

One of the authors reported financial links with Elixir Pharmaceuticals, a company that conducts aging research, but no other potential conflicts were reported.

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.